ライフサイエンスコーパス: TSC1

1 e negative regulators, tuberous sclerosis 1 (Tsc1).

2 mor suppressor tuberous sclerosis complex 1 (TSC1).

3 established BCa genes (TP53, RB1, CDKN2A and TSC1).

4 with conditional alleles of each of Tp53 and Tsc1.

5 in 1 (Hap1) as a novel functional partner of Tsc1.

6 ns in the network increases with the loss of Tsc1.

7 unction downstream of the canonical PI3K/AKT/TSC1-2 pathway.

8 However, the relationship between TSC1/2 and HIF1a and the function of HIF1a in TSC neuron

9 thelial phenotype of TSC astrocytes suggests TSC1/2 and mTOR tune the phosphorylation level of cateni

10 Differences between Tsc1/2 and Pten function become apparent at later stages

11 Our data suggest targeting TSC1/2 as a strategy for boosting antitumor immune thera

12 Loss of Tsc1/2 autonomously increases p4EBP and decreases pAKT l

13 ogether, our findings indicate that neuronal Tsc1/2 complex activity is required for the coordinated

14 d alphaB-crystallin has an essential role in TSC1/2 complex deficiency-mediated tumorigenesis, and in

15 TOR) through the tuberous sclerosis complex (TSC1/2 complex), as a new molecular target of NFATc3.

16 nd requires the Ssp2 (AMPKalpha) kinase, the Tsc1/2 complex, and Rhb1 GTPase.

17 ortant role in health and aging, the role of TSC1/2 in aging has not been fully investigated.

18 TSC1/2 negatively regulate the function of mTOR, which i

19 In this study, we demonstrate that neuronal TSC1/2 orchestrates a program of oligodendrocyte maturat

20 TSC1/2 protein complex negatively regulates the mammalia

21 nents (for example, PTEN loss, PIK3CA, AKT1, TSC1/2) are common in bladder cancer, yet small-molecule

22 tivating mutations of the TSC1/TSC2 complex (TSC1/2) cause tuberous sclerosis (TSC), a hereditary syn

23 The tuberous sclerosis complex 1/2 (TSC1/2) is an endogenous regulator of the mechanistic ta

24 Tuberous sclerosis complex-1 or 2 (TSC1/2) mutations cause white matter abnormalities, incl

25 tively feed back to mTORC1 through an AMPK-, TSC1/2-, and Rag-independent mechanism by regulating mTO

26 Surprisingly, unlike AMPK-, Lkb1- or Tsc1/2-deficient cells, FoxO-deficient cells exhibit dec

27 vel, high mTORC1-driven translation rates in TSC1/2-deficient cells, unlike wild-type cells, sensitiz

28 survival, suggesting the manipulation of the TSC1/2-mTOR pathway as a therapeutic strategy for mast c

29 s complex 1/2-mammalian target of rapamycin (TSC1/2-mTOR) signaling in mast cells is unknown.

30 that the UPR could be targeted to eradicate TSC1/2-null cells during patient therapy.

31 /B GTPases and for RalGAPalpha/beta, but not Tsc1/2.

32 isposition syndrome) cascade upstream of the TSC1/2/mTOR pathway and thus likely to be a tumor suppre

33 The C-terminal domain of Tsc1 (998-1,164 aa) forms a homodimer and binds to both

34 in this study that the tuberous sclerosis 1 (TSC1), a negative regulator of mTOR signaling, plays a c

35 We describe here that tuberous sclerosis 1 (Tsc1), a regulator of mTOR signaling, plays a crucial ro

36 Surprisingly, targeted mutation of Tsc1, a negative regulator of mTORC1, caused a broad red

37 Expression profiling analysis reveals that Tsc1 ablation induces prominent endoplasmic reticulum (E

38 Collectively, these studies suggest that TSC1 acts as an important checkpoint for maintaining imm

39 oligodendrocytes, we reveal that deletion of Tsc1 affects oligodendroglia differently depending on th

40 n of the gene encoding tuberous sclerosis 1 (TSC1), an upstream negative regulator of mTOR, resulted

41 this issue, Park et al. examine the role of TSC1, an mTOR signaling regulator, in T cell differentia

42 enic mutations in 13 patients/families (6 in TSC1 and 7 in TSC2), 5 of which were novel.

43 um homeostasis and demonstrates that loss of TSC1 and activation of mTORC1 results in dedifferentiati

44 indows in 5 genes; DNA methylation of SMAD1, TSC1 and AKT1 showed significant difference across breed

45 enhanced by Treg-specific double deletion of Tsc1 and Foxo3a.

46 ular zone (SVZ) of neonatal mice, we deleted Tsc1 and generated olfactory lesions containing misplace

47 in tissues of forebrain-specific conditional TSC1 and phosphatase and tensin homlog knock-out mice, b

48 onset of any strain, indicating that loss of Tsc1 and Pten have synergistic effects on tumorigenesis.

49 cell proliferation, in the renal tubules of Tsc1 and rpS6 double-mutant mice.

50 campal neurons induces the downregulation of Tsc1 and stimulates the activity of mTORC1, as reflected

51 However, the roles of Tsc1 and the sequelae of Tsc1 dysfunction in the cerebel

52 were established, which showed loss of both Tsc1 and Tp53, with mammalian target of rapamycin comple

53 The tuberous sclerosis proteins TSC1 and TSC2 are key integrators of growth factor signa

54 The TSC proteins Tsc1 and Tsc2 control the mTORC1 signaling pathway in di

55 Using Tsc1 and Tsc2 floxed alleles and a radial glial transgen

56 The tumor suppressors Tsc1 and Tsc2 form the tuberous sclerosis complex (TSC),

57 did not reveal any genomic rearrangements in TSC1 and TSC2 in the samples with no mutations identifie

58 BC1D7 knockdown decreases the association of TSC1 and TSC2 leading to decreased Rheb-GAP activity, wi

59 r knowledge, this is the first comprehensive TSC1 and TSC2 mutational analysis carried out in TSC pat

60 The heterodimeric TSC complex, consisting of Tsc1 and Tsc2 proteins, regulates the activity of the TO

61 compare and contrast the brain phenotypes of Tsc1 and Tsc2 single and double mutants.

62 complex (TSC) is caused by mutations in the TSC1 and TSC2 tumor suppressor genes.

63 method to search for SS/L interactions with TSC1 and TSC2, the two tumor suppressors underlying tube

64 genes implicated in disease development are TSC1 and TSC2.

65 tation in one of two tumor suppressor genes, TSC1 and TSC2.

66 driver (FVB-Tg(GFAP-cre)25Mes/J), we deleted Tsc1 and/or Tsc2 in radial glial progenitor cells.

67 Tsc1(-/-) and Tsc2(-/-) mouse embryonic fibroblasts expr

68 Tuberous sclerosis complex 1 (TSC1) and TSC2 are suppressors of mechanistic target of

69 ase B1 (LKB1), tuberous sclerosis complex 1 (TSC1) and tuberous sclerosis complex 2 (TSC2), leads to

70 including PIK3CA, ATM, CDKN2A, SF3B1, SUFU, TSC1, and CYLD.

71 Mutations in TSC1, and possibly other genes, may predict for sensitiv

72 he biologic basis for the difference between TSC1- and TSC2-based disease is unclear.

73 LKB1 and TSC2, but not TSC1, are required for PERK-mediated inhibition of mamma

74 In this study, we identify TSC1 as a component of the transforming growth factor be

75 Our findings establish an active role for Tsc1 as a facilitator of Hsp90-mediated folding of kinas

76 Previous studies have identified Tsc1 as a regulator of hippocampal neuronal morphology a

77 We hypothesized that thalamic deletion of Tsc1 at distinct stages of mouse brain development would

78 IRI) in normal and steatotic liver using Alb-TSC1(-/-) (AT) and Alb-mTOR(-/-) (Am) transgenic mice.

79 that the TSC2 N terminus interacts with the TSC1 C terminus to mediate complex formation.

80 ia ablation of tuberous sclerosis complex 1 (TSC1), causes hypomyelination characterized by downregul

81 th collecting-duct (CD)-specific ablation of TSC1 (CDTsc1KO) had greater mTOR complex 1 (mTORC1) acti

82 ent neurons, as well as in a neuron-specific Tsc1 conditional knock-out mouse model, and show differe

83 ) structure-related gene expression, whereas Tsc1 conditional knockout mice exhibited changes in gene

84 In addition, Tsc1 conditional knockout mice presented severely disorg

85 was significantly reduced in both Raptor and Tsc1 conditional knockout mice, albeit with variations i

86 y activation are also found in the brains of Tsc1-conditional mouse models and in cortical tubers res

87 Transcriptome analysis indicated that Tsc1 coordinated gene expression programs underlying imm

88 Thus, TSC1 couples Akt activity to TGF-beta-Smad2/3 signaling.

89 Activation of mTOR by leucine or deletion of TSC1 decreased expression of brown adipocyte-related gen

90 Furthermore, TSC1 deficiency appears to cause impaired induction of e

91 Moreover, Tsc1 deficiency caused DC spontaneous maturation but a p

92 expressing a cognate antigen, we found that TSC1 deficiency impairs antigen-specific CD8 T cell resp

93 Tsc1 deficiency suppressed the generation of memory-prec

94 TSC1-deficiency results in impaired mast cell degranulat

95 Poor expansion of TSC1-deficient cells was associated with defects in surv

96 Mechanistically, Tsc1-deficient DCs exhibited increased glycolysis, mitoc

97 ble for decreased CIITA/MHC-II expression in TSC1-deficient DCs.

98 Moreover, TSC1-deficient iNKT cells display enhanced antitumor imm

99 inance of iNKT-17 cells in the population of TSC1-deficient iNKT cells.

100 TSC1-deficient macrophages produce elevated proinflammat

101 d-type counterparts and antigen rechallenge, TSC1-deficient memory cells showed moderate defects in e

102 They found that enhanced mTOR activity in Tsc1-deficient T cells promotes Th1 and Th17 differentia

103 Resistance of TSC1-deficient T cells to anergy is correlated with incr

104 Tsc1-deficient Tregs had impaired suppressive activity i

105 rpS6 suppresses cystogenesis and fibrosis in Tsc1-deleted kidneys.

106 Tsc1 deletion at this early stage is unique in causing b

107 Both leucine and TSC1 deletion blocked nesfatin-1-induced up-regulation o

108 ssociation and Akt phosphorylation in liver, Tsc1 deletion failed to cause glucose intolerance or pro

109 Moreover, Tsc1 deletion failed to stimulate phospho-Ser-302 or oth

110 Following acute Tsc1 deletion from hepatocytes, Akt phosphorylation, but

111 Tsc1 deletion from NG2(+) OPCs accelerated remyelination

112 Conversely, Tsc1 deletion from proteolipid protein (PLP)-positive ol

113 onstitutive activation of mTOR signalling by Tsc1 deletion in the oligodendrocyte lineage results in

114 Conditional Tsc1 deletion in Tregs impaired their suppressive activi

115 during remyelination in which the timing of Tsc1 deletion is a critical determinant of its effect on

116 Furthermore, Tsc1 deletion led to excessive mTORC1 activity and dysre

117 We find that neuron-specific Tsc1 deletion results in an increase in CTGF secretion t

118 We show that mosaic Tsc1 deletion within thalamic precursors at embryonic da

119 eveloped epilepsy a few days after biallelic Tsc1 deletion.

120 complex 1 (mTORC1) activation, we find that Tsc1(Delta/Delta) macrophages are refractory to IL-4-ind

121 h myeloid lineage-specific deletion of Tsc1 (Tsc1(Delta/Delta)) leads to constitutive mTOR complex 1

122 Our data indicate that TSC1-dependent control of mTORC1 is crucial for terminal

123 Hyperactive Akt specifically activates TSC1-dependent cytostatic Smad signaling to induce growt

124 ic TGF-beta signaling by inhibiting Akt- and TSC1-dependent Smad activation.

125 nant of newborn neuron survival and that its TSC1-dependent up-regulation gave Tsc1(null) neurons a s

126 -derived NO is associated with impaired TSC2/TSC1 dimerization, mTOR pathway activation, and prolifer

127 wever, the roles of Tsc1 and the sequelae of Tsc1 dysfunction in the cerebellum have not been investi

128 rization of TSC2 with its inhibitory partner TSC1, enhancing GTPase activity of its target Ras homolo

129 Here, we determined that mice lacking TSC1 exhibit a developmental block of iNKT differentiati

130 data demonstrated that moderate increase of TSC1 expression can enhance overall health, particularly

131 In vivo, suppression of TSC1 expression increased locomotor activity and decreas

132 inheritance-related clusters related to PTEN/TSC1/FMR1 and mTor/PI3K regulation.

133 ronger effector-like phenotype compared with Tsc1-/- Foxp3+ Tregs.

134 Here, we provide evidence that deletion of Tsc1 from OPCs, but not differentiating oligodendrocytes

135 Here, TSC1 functions independently of TSC2.

136 Hyperactivation of mTORC1 via TSC1 gene deletion in chondrocytes causes uncoupling of

137 Biallelic Tsc1 gene deletion was induced in adult Tsc1 heterozygou

138 ly ablated the tuberous sclerosis complex 1 (Tsc1) gene, an mTOR inhibitor, in the rods of the Pde6b(

139 ogically linked to mutations in the tsc2 and tsc1 genes in the case of LAM.

140 used by heterozygous mutations in either the TSC1 (hamartin) or the TSC2 (tuberin) gene.

141 terozygous mutations in either of two genes, TSC1 (hamartin) or TSC2 (tuberin), are responsible for m

142 ct of the tuberous sclerosis complex 1 gene (TSC1), hamartin, is selectively induced by ischemia in h

143 biallelic inactivation of either TSC genes (TSC1, hamartin or TSC2, tuberin), an event that is impli

144 Similarly, mice lacking neuronal Tsc1 have a hypomyelination phenotype.

145 transcriptional activity when compared with Tsc1 heterozygote neurons and a marked resistance to cel

146 ells (NPCs) of tuberous sclerosis complex 1 (Tsc1) heterozygote mice leads to heterotopia and abnorma

147 elic Tsc1 gene deletion was induced in adult Tsc1 heterozygous and wild-type mice.

148 its negative regulator tuberous sclerosis 1 (Tsc1) impaired DC development in vivo and in vitro, asso

149 channel 4 (CLIC4) and tuberous sclerosis 1 (TSC1), important innate immunity regulators.

150 Mice with specific deletion of Tsc1 in antigen-experienced CD8(+) T cells evoked normal

151 aling induced by acute biallelic deletion of Tsc1 in healthy adult mice.

152 Deficiency of TSC1 in iNKT cells results in resistance to alpha-GalCer

153 ption factor Myc, highlighting a key role of Tsc1 in modulating metabolic programming of DC different

154 le deletion system, we show that deletion of Tsc1 in mouse primary mammary tumor cells, either before

155 TSC1 in POMC neurons, but not those lacking TSC1 in NPY/AgRP neurons, were obese.

156 These findings demonstrate new roles for Tsc1 in PC function and define a molecular basis for a c

157 ung mice lacking the mTOR-negative regulator TSC1 in POMC neurons, but not those lacking TSC1 in NPY/

158 Our results reveal a critical role of TSC1 in regulating innate immunity by negative control o

159 evealed an essential cell-intrinsic role for TSC1 in T cell survival, quiescence, and mitochondrial h

160 The loss of Tsc1 in the mouse neural tube increases the number of th

161 evidence of a CD8 T cell-intrinsic role for TSC1 in the regulation of antigen-specific primary and m

162 of the tuberous sclerosis complex protein 1 (Tsc1) in renal proximal tubules induced strikingly enlar

163 eurons lacking tuberous sclerosis complex 1, Tsc1, in a mouse model of genetic epilepsy.

164 tive regulators of mTORC1, including TSC2 or TSC1, in developing SCs of mutant mice.

165 tudy, we examine the role of its suppressor, TSC1, in the regulation of antigen-specific primary and

166 se was characterized by loss of 9q including TSC1, increased KI67 labeling index, upregulated glycoly

167 TSC1 interacts with the TGF-beta receptor complex and Sm

168 Here, we report that TSC1 is a critical regulator for mTOR signaling in mast

169 Together, these findings reveal that TSC1 is a critical regulator of mast cell activation and

170 Here, we show that Tsc1 is a new co-chaperone for Hsp90 that inhibits its A

171 Together, our data indicate that TSC1 is crucial for T-cell anergy by inhibiting mTORC1 s

172 set of these phenotypes occurs when thalamic Tsc1 is deleted at a later embryonic stage.

173 Using two different mouse models in which Tsc1 is deleted by Cre expression in oligodendrocyte pro

174 mor suppressor tuberous sclerosis complex 1 (TSC1) is a critical regulator of DC function for both in

175 The tuberous sclerosis complex 1 (TSC1) is a tumor suppressor that inhibits the mammalian

176 The tumor suppressor tuberous sclerosis 1 (TSC1) is an important negative regulator of mTOR signali

177 vivo recapitulate the phenotypes induced by Tsc1 knockdown.

178 d expression of eomesodermin among activated TSC1 knockout cells.

179 L-Tsc1 KO mice displayed reduced locomotor activity, body

180 Using RVF5, we show that Tsc1 KO neurons exhibit increased activity relative to w

181 In Tsc1 KO neurons, weakened inhibition caused by deregulat

182 siology, we generated liver-specific Tsc1 (L-Tsc1 KO) knockout mice.

183 body physiology, we generated liver-specific Tsc1 (L-Tsc1 KO) knockout mice.

184 Tsc1 loss increased retinal angiogenesis in neonates and

185 Hyperactivation of mTORC1 through Tsc1 loss resulted in a significant increase in ARF expr

186 These findings establish a Tsc1-mediated checkpoint in linking immune signaling and

187 This study highlights that TSC1-mediated control of mTOR activity impinges on the b

188 cific GluN2C/D antagonists block seizures in Tsc1(+/-) mice in vivo and in vitro.

189 Here we report that tuberless heterozygote Tsc1(+/-) mice show functional upregulation of cortical

190 Thus, TSC1-mTOR signalling acts as an important checkpoint for

191 ogether, our data reveal unexpected roles of TSC1/mTOR that control multifaceted functions of DCs.

192 ficient cells, both in culture and in mosaic Tsc1 mutant mice.

193 ice recapitulate the pathologies observed in Tsc1 mutant mice.

194 These data show that Tsc1-mutant cells from the neonatal and juvenile SVZ gen

195 ockin of a nonphosphorylatable rpS6 in these Tsc1-mutant mice exacerbated cystogenesis and caused dra

196 nregulation by mTORC1 in the cystogenesis of Tsc1 mutants.

197 and partially rescues myelination defects in Tsc1 mutants.

198 109 additional bladder cancers examined, and TSC1 mutation correlated with everolimus sensitivity.

199 detected in 53% (10 of 19) of patients with TSC1 mutation, 65% (11 of 17) of patients with TSC2 muta

200 Targeted sequencing revealed TSC1 mutations in about 8% of 109 additional bladder can

201 bitors or small hairpin RNA, suggesting that TSC1 negatively controls TLR responses through both mTOR

202 d that its TSC1-dependent up-regulation gave Tsc1(null) neurons a survival advantage, despite their m

203 rated olfactory lesions containing misplaced Tsc1(null) neurons as previously reported.

204 f HIF1a activity and its function in newborn Tsc1(null) neurons in a mouse model of TSC.

205 FLNA, and decreasing MEK-ERK1/2 signaling in Tsc1(null) neurons rescued dendritic defects.

206 Surprisingly, FLNA overexpression in Tsc1(null) neurons was dependent on MEK1/2 but not mTOR

207 In Tsc1(null) neurons, knocking down FLNA in vivo prevented

208 HIF1a constructs resulted in 80-90% loss of Tsc1(null) newborn neurons although sparing SVZ stem cel

209 exosomes derived from tuberous sclerosis 1 (Tsc1)-null cells transform phenotypes of neighboring wil

210 of gamma-secretase complex presenilin 1 from Tsc1-null cells to wild-type cells leading to the activa

211 ner that they become functionally similar to Tsc1-null cells.

212 on of fibroblast growth factor receptor 1 in Tsc1-null mice suppressed Akt and mitogen-activated prot

213 A fate-mapping study revealed that Tsc1-null Tregs that lost Foxp3 expression gained a stro

214 ed autophagy, was increased significantly in Tsc1-null tumor cells.

215 ey inhibitory components upstream of mTORC1, TSC1 or PTEN, in mouse SC development, adult homeostasis

216 emonstrate that reduced expression of either TSC1 or TSC2 causes reduced pigmentation through mTORC1

217 Loss of Tsc1 or Tsc2 copies the progressive Lkb1(cko) phenotype,

218 ligodendroglia and hypomyelination seen with Tsc1 or Tsc2 deletion in the oligodendrocyte lineage dur

219 (LAM) as a consequence of biallelic loss of TSC1 or TSC2 gene function express melanoma differentiat

220 ) is a disorder arising from mutation in the TSC1 or TSC2 gene, characterized by the development of h

221 disorder that results from a mutation in the TSC1 or TSC2 genes leading to constitutive activation of

222 TSC is caused by the loss of either the TSC1 or TSC2 genes that normally regulate the mammalian

223 by loss of function mutations in either the TSC1 or TSC2 genes, which regulate mTOR kinase activity.

224 Patients are born with TSC1 or TSC2 mutations, and somatic inactivation of wild

225 is a genetic disorder caused by mutations in TSC1 or TSC2 resulting in hyperactivity of the mammalian

226 ssociated with inactivating mutations in the TSC1 or TSC2 tumor suppressor genes.

227 TSC), caused by dominant mutations in either TSC1 or TSC2 tumour suppressor genes is characterized by

228 Inactive mutation of either TSC1 or TSC2 unleashes mTOR signaling and consequently c

229 ons in the tuberous sclerosis complex genes (TSC1 or TSC2), resulting in hyperactive mammalian Target

230 tations in tuberous sclerosis complex genes (TSC1 or TSC2).

231 e caused by inactivating mutations in either TSC1 or TSC2, and the TSC protein complex is an essentia

232 berous sclerosis complex tumour suppressors, TSC1 or TSC2, or physiological activation of mTORC1 in r

233 ivation of mTORC1, although none had loss of TSC1 or TSC2.

234 c neurogenesis due to inherited mutations in Tsc1 or Tsc2.

235 n mutations in tuberous sclerosis complex 1 (TSC1) or TSC2 genes, causes protein synthesis dysregulat

236 sion of alphaB-crystallin was upregulated in Tsc1-/- or Tsc2-/- mouse embryonic fibroblasts, Eker rat

237 pathway is deregulated by mutations in MTOR, TSC1, PIK3CA, and PTEN in approximately 20% of ccRCCs.

238 These findings indicate that Tsc1 prevents aberrant renal growth and tumorigenesis by

239 luation of purified iNKT cells revealed that TSC1 promotes T-bet, which regulates iNKT maturation, bu

240 pG sites showed significant correlation with TSC1 protein expression.

241 TSC1 regulates TGF-beta-induced Smad2/3 phosphorylation

242 uses growth arrest, concomitant knockdown of Tsc1 restores mTORC1 activity and proximal tubular size.

243 Deficiency of TSC1 resulted in enhanced T-cell proliferation and cytok

244 We show in this study that deficiency of TSC1 results in enhanced activation of not only mTOR com

245 sults demonstrate that the interplay between Tsc1-Rheb-mTORC1 signaling and Myc-dependent bioenergeti

246 didate SNPs (rs6433115 at LRP2, rs1050700 at TSC1, rs249942 at PALB2, and rs9827843 at ROBO2) did not

247 ing restricts dendritic extent, with Src and Tsc1 serving as downstream mediators.

248 Suppression of hamartin expression with TSC1 shRNA viral vectors both in vitro and in vivo incre

249 Further, Tsc1 signaled through Rheb to down-regulate mTORC1 for p

250 In contrast, Tsc1 single-mutant mice were all alive and had far fewer

251 Furthermore, pharmacologic treatment of Tsc1 single-mutant mice with rapamycin reduced hyperphos

252 Tsc1 stabilizes Tsc2; however, the precise mechanism inv

253 rrent study, a constitutive TSC1 transgenic (Tsc1 (tg) ) mouse model was generated and characterized.

254 Tsc1 (tg) mice are more tolerant to exhaustive exercises

255 The female Tsc1 (tg) mice exhibit a higher fat to lean mass ratio a

256 Tsc1 (tg) mice have less fibrosis and inflammation in ag

257 e lifespan increased significantly in female Tsc1 (tg) mice, but not in male Tsc1 (tg) mice.

258 ly in female Tsc1 (tg) mice, but not in male Tsc1 (tg) mice.

259 n contrast, mTORC2 signaling was enhanced in Tsc1 (tg) mice.

260 indings define a novel link between Hap1 and Tsc1 that regulates neuronal mTORC1 signaling and neuron

261 creases its affinity for Hsp90 and displaces Tsc1, thereby providing a mechanism for equilibrium betw

262 ucible endothelial-cell-specific deletion of Tsc1 to examine mTORC1 signaling in lymphangiosarcoma.

263 In the current study, a constitutive TSC1 transgenic (Tsc1 (tg) ) mouse model was generated a

264 Elevated IL-17 production in Tsc1-/- Treg cells was reversed by in vivo knockdown of

265 n which myeloid lineage-specific deletion of Tsc1 (Tsc1(Delta/Delta)) leads to constitutive mTOR comp

266 The tuberous sclerosis 1 (TSC1)/TSC2 complex negatively regulates the activity of

267 al, whereas 21% uRCC with mutations of MTOR, TSC1, TSC2 or PTEN and hyperactive mTORC1 signalling are

268 d with expression of the upstream regulators TSC1, TSC2, AKT, p-AKT, PDPK1, PTEN, PIK3R1, or PIK3CA.

269 fumarate hydratase, succinate dehydrogenase, TSC1, TSC2, and TFE3 genes, have significantly altered t

270 sis complex (TSC) tumor suppressors form the TSC1-TSC2 complex, which limits cell growth in response

271 ted and ubiquitous third core subunit of the TSC1-TSC2 complex.

272 The mammalian Tsc1-Tsc2 GTPase activating protein (GAP) heterodimer is

273 characterize the molecular requirements for TSC1-TSC2 interactions and analyze pathological point mu

274 Unexpectedly, we also found that Tsc1-Tsc2 loss activated RalA/B independently of Rheb-mT

275 ormal proliferation and induces apoptosis of TSC1-TSC2-deficient cells, both in culture and in mosaic

276 ugh the PI3K-Akt pathway, which inhibits the TSC1-TSC2-TBC1D7 complex (the TSC complex) to turn on Rh

277 ares sequence and structural similarity with Tsc1-Tsc2.

278 ves MTOR activation; however, second hits to TSC1/TSC2 are not always observed.

279 Inactivating mutations of the TSC1/TSC2 complex (TSC1/2) cause tuberous sclerosis (TSC

280 tional kinase is an upstream effector of the TSC1/TSC2 complex that regulates mTOR signaling.

281 DAPK1 mediated the disruption of the TSC1/TSC2 complex, resulting in activation of the mTOR p

282 utation in tumor suppressor genes coding the TSC1/TSC2 complex, resulting in the hyperactivation of m

283 , which develops as a result of mutations in TSC1/TSC2 genes in TSC patients, because we observed the

284 cluding Lgals3 relevant for human disease of TSC1/TSC2 inactivation and mTORC1 hyperactivity.

285 Increased mTORC1 signaling from TSC1/TSC2 inactivation is found in cancer and causes tub

286 To see whether TSC1/TSC2 loss was a common genetic event in human mesot

287 Double Tsc1/Tsc2 mutants died earlier than single mutants, and

288 s was also increased in bladder cancers with TSC1/TSC2 mutations in the TCGA database.

289 ntified germline and second-hit mutations in TSC1/TSC2 using next-generation sequencing.

290 us sclerosis complex tumor-suppressor genes (TSC1/TSC2) that cause LAM, a multisystem disease charact

291 ncy mutated genes (eg, AXIN1, ARID2, ARID1A, TSC1/TSC2, RPS6KA3, KEAP1, MLL2), help define some of th

292 e further delineate that YAP accumulation in TSC1/TSC2-deficient cells is due to impaired degradation

293 ained activation of the MEK-ERK pathway in a TSC1/TSC2/TBC1D7 protein complex and mTORC1-independent

294 mutations was a loss-of-function mutation in TSC1 (tuberous sclerosis complex 1), a regulator of mTOR

295 dney-specific inactivation of either Pkd1 or Tsc1 using an identical Cre (KspCre) results in aggressi

296 e mTORC1 in mouse tissue, we deleted hepatic Tsc1 using Cre adenovirus.

297 accumulation by directly targeting Mdm2 and TSC1, which are negative regulators of p53 and the mTOR

298 Mutations of RAS, PTEN, and TSC1, which cause mTORC1 hyperactivation, enhance immuno

299 ntal genetic disorder caused by mutations in TSC1, which results in epilepsy, autism, and intellectua

300 n general, TSC2 disease was more severe than TSC1, with more subependymal giant cell astrocytomas and

301 Cell-specific loss of Tsc1 within nestin-expressing cells in adult mice leads